Is COMP p.Asp4Ala (c.11A>C) pathogenic?

COMP p.Asp4Ala (c.11A>C) is classified Conflicting classifications of pathogenicity in COMP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.0424); Ultra-rare (popmax 0.0331%, mid); Associated with pseudoachondroplasia.

What condition is associated with COMP p.Asp4Ala (c.11A>C)?

COMP p.Asp4Ala (c.11A>C) is associated with pseudoachondroplasia, connective tissue disorder, multiple epiphyseal dysplasia type 1 (ClinVar).

How common is COMP p.Asp4Ala (c.11A>C) in the general population?

COMP p.Asp4Ala (c.11A>C) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

How is Pseudoachondroplasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COMP p.Asp4Ala (c.11A>C)?

AlphaMissense predicts likely benign (score 0.0424) — an in-silico prediction, not a clinical call.

COMP p.Asp4Ala

c.11A>C · rs370458957 · VCV888609

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0424 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pseudoachondroplasia

Computational evidence

Protein change
AlphaMissense	0.0424	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -2.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -2.7, phastCons 0.76
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	8.774	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0331% Middle Eastern · 2/6,038 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.0132% 210/1,593,450 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0372%	2,687
Middle Easterngrpmax	0.0331%	3,019
African / African-American	0.0321%	3,114
European (non-Finnish)	0.0127%	7,858
South Asian	0.00908%	11,008
Ashkenazi Jewishnot grpmax-eligible	0.00686%	14,569
Admixed American	0.00351%	28,454

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COMP
Protein: p.Asp4Ala
Coding: c.11A>C
MANE Select: NM_000095
dbSNP: rs370458957
Type: single nucleotide variant
Location: chr19:18791259 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB

Full COMP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pseudoachondroplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: connective tissue disorder multiple epiphyseal dysplasia type 1

For Pseudoachondroplasia (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn555Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp269Gly Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp273Val Likely pathogenic ★★ same condition
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp349His Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/comp-p-asp4ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown